Brand Names: U.S.

Acetadote

Cetylev

Pharmacologic Category

Antidote

Mucolytic Agent

Pharmacology

Acetaminophen overdose: Acetylcysteine acts as a hepatoprotective agent by restoring hepatic glutathione, serving as a glutathione substitute, and enhancing the nontoxic sulfate conjugation of acetaminophen.

Mucolytic: Exerts mucolytic action through its free sulfhydryl group which opens up the disulfide bonds in the mucoproteins thus lowering mucous viscosity.

Distribution

Vdss: 0.47 L/kg

Metabolism

Undergoes extensive first pass metabolism to form cysteine and disulfides (N,N-diacetylcysteine and N-acetylcysteine); cysteine is further metabolized to form glutathione and other metabolites

Duration of Action

Half-Life Elimination

Protein Binding

66% to 87%

Use: Labeled Indications

Acetaminophen overdose: To prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion (RSTI).

Contraindications

Hypersensitivity to acetylcysteine or any component of the formulation.

Effervescent tablet (Cetylev): There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Acetaminophen overdose: Only the 72-hour oral and 21-hour IV regimens are FDA approved. Ideally, in patients with acute acetaminophen ingestion, treatment should begin within 8 hours of ingestion or as soon as possible after ingestion. In patients with a suspected acute ingestion where the time of ingestion is unknown, the concentration is unobtainable or uninterpretable within 8 hours of ingestion, the patient presents >8 hours after ingestion, or there is clinical evidence of toxicity, initiate treatment immediately and re-evaluate the need for acetylcysteine upon receipt of the results (if applicable). In patients who present following RSTI and treatment is deemed appropriate, acetylcysteine should be initiated immediately. Regardless of the treatment regimen selected, serum acetaminophen concentrations, liver function, and clinical status should be evaluated during and prior to the end of the treatment regimen to determine if treatment discontinuation is appropriate. In patients who continue to experience symptoms of hepatotoxicity or elevated liver function tests at the conclusion of a 72-hour oral or 21-hour IV regimen, extending the treatment course may be appropriate; however, when and to which patients additional doses should be administered is unclear. Possible candidates for extended therapy include patients with a suspected massive overdose, concomitant ingestion of other substances, or patients with preexisting liver disease. In patients with persistently elevated acetaminophen concentrations, persistently elevated liver function tests, or an elevated INR, additional acetylcysteine should be administered. Typically, an additional "third dose" or "third bag" (IV: 100 mg/kg [maximum: 10 g] infused over 16 hours) is administered; however, this dose may be inadequate in some patients (Rumack 2012). It is critical that there is no delay in the administration of the loading dose of acetylcysteine and no delays in the administration of bags two and three (Bailey 2016). A two-bag regimen with the same total dose of 300 mg/kg has been used, but is not FDA-approved (Bateman 2014; Isbister 2016; Wong 2016). Consultation with a poison control center or clinical toxicologist is highly recommended to determine optimal patient care.

Note: There is no reason to withhold activated charcoal in a patient with an acetaminophen overdose. If activated charcoal is administered within 1 to 2 hours postingestion of acetaminophen, it may provide additional hepatoprotection in patients requiring NAC treatment for acetaminophen overdose (Spiller 2007).

Oral: (Effervescent tablets [Cetylev]; solution for oral administration): Note: Consultation with a poison control center or clinical toxicologist is highly recommended when considering the discontinuation of oral acetylcysteine prior to the conclusion of a full 18-dose course of therapy.

Inhalation, nebulization (face mask, mouth piece, tracheostomy): Acetylcysteine 10% and 20% solution (dilute 20% solution with sodium chloride or sterile water for inhalation); 10% solution may be used undiluted: 3 to 5 mL of 20% solution or 6 to 10 mL of 10% solution until nebulized given 3 to 4 times/day; dosing range: 1 to 10 mL of 20% solution or 2 to 20 mL of 10% solution every 2 to 6 hours

Inhalation, nebulization (tent, croupette): Dose must be individualized; may require up to 300 mL solution/treatment

Direct instillation:

Into tracheostomy: 1 to 2 mL of 10% to 20% solution every 1 to 4 hours

Through percutaneous intratracheal catheter: 1 to 2 mL of 20% or 2 to 4 mL of 10% solution every 1 to 4 hours via syringe attached to catheter

Diagnostic bronchogram: Nebulization or intratracheal: 1 to 2 mL of 20% solution or 2 to 4 mL of 10% solution administered 2 to 3 times prior to procedure

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Acetaminophen poisoning: Infants, Children, and Adolescents: Only the 72-hour oral and 21-hour IV regimens are FDA approved. Ideally, in patients with an acute acetaminophen ingestion, treatment should begin within 8 hours of ingestion or as soon as possible after ingestion. In patients with a suspected acute ingestion where the time of ingestion is unknown, the serum acetaminophen concentration is unobtainable or uninterpretable within 8 hours of ingestion, the patient presents >8 hours after ingestion, or there is clinical evidence of toxicity, initiate treatment immediately and re-evaluate the need for acetylcysteine upon receipt of the results (if applicable). In patients who present following repeated supratherapeutic ingestions (RSTI) and treatment is deemed appropriate, acetylcysteine should be initiated immediately. Regardless of the treatment regimen selected, serum acetaminophen concentrations, liver function, and clinical status should be evaluated during and prior to the end of the treatment regimen to determine if treatment discontinuation is appropriate. In patients who continue to experience symptoms of hepatotoxicity or elevated liver function tests at the conclusion of a 72-hour oral or 21-hour IV regimen, extending the treatment course may be appropriate; however, when and to which patients additional doses should be administered is unclear. Possible candidates for extended therapy include patients with a suspected massive overdose, concomitant ingestion of other substances, or patients with preexisting liver disease. In patients with persistently elevated acetaminophen concentrations, persistently elevated liver function tests, or an elevated INR, additional acetylcysteine should be administered. Typically, an additional "third dose" or "third bag" (IV: 100 mg/kg [maximum dose: 10 g/dose] infused over 16 hours) is administered; however, this dose may be inadequate in some patients (Rumack 2012). Consultation with a poison control center or clinical toxicologist is highly recommended to determine optimal patient care.

Oral: Effervescent tablet (Cetylev) or solution for oral administration (using injectable/nebulizer formulation): There is no data for use of the OTC supplement tablets for acetaminophen poisoning. Dosing below is based on effervescent tablet (Cetylev) or a solution for oral administration that is prepared from the solution for oral inhalation: 72-hour regimen: Consists of 18 doses; total dose delivered: 1,330 mg/kg

Loading dose: 140 mg/kg; maximum dose: 15 g/dose

Maintenance dose: 70 mg/kg every 4 hours for 17 doses; maximum dose: 7.5 g/dose; repeat dose if emesis occurs within 1 hour of administration; Note: Consultation with a poison control center or clinical toxicologist is highly recommended when considering the discontinuation of oral acetylcysteine prior to the conclusion of a full 18-dose course of therapy.

Infants: 1 to 2 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 2 to 4 mL of 10% solution (undiluted); administer 3 to 4 times daily

Children: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6 to 10 mL of 10% solution (undiluted); administer 3 to 4 times daily

Adolescents: 3 to 5 mL of 20% solution (may be further diluted with sodium chloride or sterile water for inhalation) or 6 to 10 mL of 10% solution (undiluted); administer 3 to 4 times daily; usual dosing range: 20% solution: 1 to 10 mL or 10% solution: 2 to 20 mL every 2 to 6 hours

Tent, croupette: 10% or 20% solution: Dose must be individualized; dose is volume of solution necessary to maintain a very heavy mist in tent or croupette; in some cases, may require up to 300 mL solution/treatment

Direct instillation: Children and Adolescents:

Endotracheal: 1 to 2 mL of 10% to 20% solution every 1 to 4 hours as needed

Children 10 years and Adolescents: 60 mL of 10% solution diluted in 60 mL juice or soda 3 times/day for 24 hours

Note: Prior to treatment, administer a phosphosoda enema. A clear liquid diet should be used during the 24-hour acetylcysteine treatment

Rectal enema: Children: Varying dosages; 100 to 300 mL of 4% to 6% solution 2 to 4 times daily; 50 mL of 20% solution 1 to 4 times daily and 5 to 30 mL of 10% to 20% solution 3 to 4 times daily have been used; rectal enemas appear to have less favorable results than oral administration (Mascarenhas 2003). Note: Higher concentrations (10% to 20%) appear to increase fluid in the bowel and lead to increased incidence of adverse effects (Perman 1975)

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Reconstitution

Effervescent tablets (Cetylev): Dissolve the effervescent tablets in the volume of water indicated below based upon patient weight; administer immediately:

1 to <20 kg: Dissolve two 2.5 g tablets in 100 mL of water to create a 50 mg/mL solution; administer an appropriate amount of this solution to deliver the calculated dose.

20 to <60 kg: Dissolve an appropriate number of tablets to deliver the calculated dose in 150 mL of water.

≥60 kg: Dissolve an appropriate number of tablets to deliver the calculated dose in 300 mL of water.

Solution for inhalation: The 20% solution may be diluted with sodium chloride or sterile water; the 10% solution may be used undiluted.

Note: Clinicians should be aware that undiluted injection solution (Acetadote) is hyperosmolar (2,600 mOsmol/L); when the diluent volume is decreased for patients ≤40 kg or requiring fluid restriction, the osmolarity of the solution may remain higher than desirable for intravenous infusion. To ensure tolerance of the infusion, osmolarity should be adjusted to a physiologically safe level (eg, ≥150 mOsmol/L in children).

Acetadote concentration: 7 mg/mL

Osmolarity in D5W: 343 mOsmol/L

Osmolarity in 1/2NS: 245 mOsmol/L

Osmolarity in SWFI: 91 mOsmol/L

Acetadote concentration: 24 mg/mL

Osmolarity in D5W: 564 mOsmol/L

Osmolarity in 1/2NS: 466 mOsmol/L

Osmolarity in SWFI: 312 mOsmol/L

Solution for oral administration: Dilute the 20% solution 1:3 with a cola, orange juice, or other soft drink to prepare a 5% solution. If being administered via a nasogastric tube or Miller-Abbott tube, water may be used as the diluent. Use within 1 hour of preparation.

Administration

Inhalation: Acetylcysteine is incompatible with tetracyclines, erythromycin, amphotericin B, iodized oil, chymotrypsin, trypsin, and hydrogen peroxide. Administer separately. Intermittent aerosol treatments are commonly given when patient arises, before meals, and just before retiring at bedtime.

Oral:

Effervescent tablets (Cetylev): Use within 2 hours of preparation. If the patient vomits within 1 hour of administration, repeat that dose. If the patient is persistently unable to retain the orally administered acetylcysteine, acetylcysteine may be administered by nasoduodenal tube. An intravenous formulation of acetylcysteine may also be considered.

Solution for oral administration: For the treatment of acetaminophen overdose, administer orally as a 5% solution. Use within 1 hour of preparation. The unpleasant odor (sulfur-like) becomes less noticeable as treatment progresses. If patient vomits within 1 hour of dose, readminister. (Note: It is helpful to put the acetylcysteine on ice, in a cup with a cover, and drink through a straw; alternatively, administer via an NG tube).

IV (Acetadote): Acetaminophen overdose:

Loading dose: Administer over 1 hour.

Second dose: Administer over 4 hours.

Third dose: Administer over 16 hours.

If the commercial IV form is unavailable, the solution for inhalation has been used; each dose should be infused through a 0.2 micron Millipore filter (in-line) over 60 minutes (Yip 1998); intravenous administration of the solution for inhalation is not USP 797-compliant.

Storage

Effervescent tablets (Cetylev): Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture. Following dissolution in water, the solution should be used within 2 hours.

Solution for inhalation/oral administration: Store unopened vials at room temperature; once opened, store under refrigeration and use within 96 hours. A color change may occur in opened vials (light purple) and does not affect the safety or efficacy.

Solution for injection (Acetadote): Store intact vials at 20°C to 25°C (68°F to 77°F). Following reconstitution, solution is stable for 24 hours at room temperature. A color change may occur in opened vials (light pink or purple) and does not affect the safety or efficacy. Discard unused portion.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Acute flushing and erythema have been reported; usually occurs within 30 to 60 minutes and may resolve spontaneously. Serious anaphylactoid reactions (some fatal) have also been reported and are more commonly associated with IV administration, but also occur with oral administration (Mroz 1997). When used for acetaminophen overdose, the incidence is reduced when the initial intravenous loading dose is administered over 60 minutes. The acetylcysteine infusion may be interrupted until the treatment of allergic symptoms is initiated; the infusion can then be carefully restarted. Treatment for anaphylactoid reactions should be immediately available. Conversely, patients with high acetaminophen concentrations (>150 mg/L) may be at a reduced risk for anaphylactoid reactions (Pakravan 2008; Sandilands 2009; Waring 2008).

• Asthma/bronchospasm: Use caution in patients with asthma or history of bronchospasm; these patients may be at increased risk of hypersensitivity reactions.

Other warnings/precautions:

• Acute acetaminophen overdose: Appropriate use: Acetylcysteine is indicated in patients with a serum acetaminophen concentration that indicates they are at "possible" risk or greater for hepatotoxicity when plotted on the Rumack-Matthew nomogram. There are several situations where the nomogram is of limited use. Serum acetaminophen concentrations obtained <4 hours postingestion are not reliable, except to document the presence of acetaminophen (Seifert 2015). Patients presenting late may have undetectable serum concentrations, despite having received a toxic dose. The nomogram is less predictive of hepatic injury following an acute overdose with an extended release acetaminophen product. The nomogram also does not take into account patients who may be at higher risk of acetaminophen toxicity (eg, alcoholics, malnourished patients, concurrent use of CYP2E1 enzyme-inducing agents [eg, isoniazid]). Nevertheless, acetylcysteine should be administered to any patient with signs of hepatotoxicity, even if the serum acetaminophen concentration is low or undetectable. Patients who present >24 hours after an acute ingestion or patients who present following an acute ingestion at an unknown time may be candidates for acetylcysteine therapy; consultation with a poison control center or clinical toxicologist is highly recommended.

• Repeated supratherapeutic ingestion (RSTI) of acetaminophen: Appropriate use: The Rumack-Matthew nomogram is not designed to be used following RSTIs. In general, an accurate past medical history, including a comprehensive acetaminophen ingestion history, in conjunction with AST concentrations and serum acetaminophen concentrations, may give the clinician insight as to the patient's risk of acetaminophen toxicity. Some experts recommend that acetylcysteine be administered to any patient with "higher than expected" serum acetaminophen concentrations or serum acetaminophen concentration >10 mcg/mL, even in the absence of hepatic injury; others recommend treatment for patients with laboratory evidence and/or signs and symptoms of hepatotoxicity (Hendrickson 2006; Jones 2000). Consultation with a poison control center or a clinical toxicologist is highly recommended.

• Oral administration: Gastrointestinal hemorrhage: Oral administration of acetylcysteine may result in nausea and vomiting, which may exacerbate vomiting associated with acetaminophen overdose. Therefore, patients at risk of gastrointestinal hemorrhage (eg, esophageal varices, peptic ulcer) may experience an even higher risk of gastrointestinal hemorrhage during therapy.

Acute ingestion: Obtain the first acetaminophen concentration 4 hours postingestion (or as soon as possible thereafter); plot on the Rumack-Matthew nomogram. In patients who have ingested an extended release formulation of acetaminophen or have coingested an agent known to delay gastric emptying, obtain a repeat serum acetaminophen measurement 4 to 6 hours following the first measurement if the original concentration (taken at 4 to 8 hours postingestion) when plotted on the Rumack-Matthew nomogram indicated that treatment was not necessary.

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Based on limited reports using acetylcysteine to treat acetaminophen overdose in pregnant women, acetylcysteine has been shown to cross the placenta and may provide protective concentrations in the fetus.

Acetylcysteine may be used to treat acetaminophen overdose in during pregnancy (Wilkes 2005). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.